This research application proposes experiments to follow up on a discovery in the Co-PI's laboratory that extracranially administered, carrier-free polyamide ("peptide") nucleic acids (PNAs) targeted to genes (either as an antisense or sense molecule), pass the blood brain barrier and the plasma membrane barrier of neurons, where they specifically inhibit the synthesis of proteins (1). This discovery has the potential of leading to the development of PNA based therapeutics that can treat a multitude of age related diseases. To extend these initial findings to genes thought to be involved in the pathogenesis of Alzheimer's disease (AD), this proposal outlines experiments that will determine whether sense or antisense PNAs targeting the mouse presenilin 1 (PS1) gene reduce presenilin expression and lead to alterations in production of the amyloid beta protein (Abeta) both in vitro and in vivo. At the present time the rules governing optimal design of a PNA targeting a particular gene are not known. We will therefore systematically evaluate the efficacy of a number of PNAs targeting different regions of the mouse presenilin 1 gene in a cell culture system. PS1 PNAs, selected based on their in vitro efficacy (as assessed by effects on PS1 protein levels and Abeta production), will then be administered by i. p injection into Tg2576 transgenic mice that are the only widely available mouse model of amyloid deposition. These experiments should i) provide vital information regarding antisense and antigene PNA design, ii) determine whether PS1 is a reasonable therapeutic target in AD, and iii) in the event that PS1 targeted PNAs lower Abeta production in vivo may eventually lead to a novel therapeutic approach to the treatment of AD.